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Paramel Varghese, GeenaORCID iD iconorcid.org/0000-0002-4589-6440
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Publications (10 of 14) Show all publications
Kardeby, C., Paramel Varghese, G., Pournara, D., Fotopoulou, T., Sirsjö, A., Koufaki, M., . . . Grenegård, M. (2019). A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition. European Journal of Pharmacology, 857, Article ID 172428.
Open this publication in new window or tab >>A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition
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2019 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 857, article id 172428Article in journal (Refereed) Published
Abstract [en]

Natural purines like ATP, ADP and adenosine have crucial roles in platelet physiology. This knowledge has been significant in drug development and today ADP receptor antagonists are widely used for prevention of thrombotic events following myocardial infarction and ischaemic stroke.

Recent studies have shown that a purine analogue bearing nitrate ester group (denoted MK128) has anti-inflammatory effects probably due to its ability to donate nitric oxide (NO). However, other pharmacological mechanisms may contribute to the observed effect. The aim of the present study was to establish the anti-platelet activity and elucidate the underlying molecular mechanism(s) of the purine analogue MK128.

We found that MK128 reduced aggregation and secretion induced by the thrombin receptor agonist SFLLRN and nearly abolished aggregation and secretion induced by thromboxane A2 (TxA2) and collagen receptor agonists. The inhibition took place despite blockage of the NO/cGMP signalling system. Furthermore, interaction between MK128 and platelet purinergic receptors did not explain the observed inhibition. Instead, we found that MK128 concentration-dependently inhibited Rho-associated kinase (ROCK), which led to decreased ROCK-dependent myosin phosphatase target subunit (MYPT)-1 phosphorylation and suppression of platelet functional responses.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Nitric oxide, Platelet inhibitor, Purinergic receptors, Rho associated protein kinase, Thromboxane A2
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:oru:diva-74650 (URN)10.1016/j.ejphar.2019.172428 (DOI)000472711200011 ()31175850 (PubMedID)2-s2.0-85066786586 (Scopus ID)
Funder
Knowledge Foundation
Note

Funding Agency:

Onassis Foundation

Available from: 2019-06-10 Created: 2019-06-10 Last updated: 2019-11-14Bibliographically approved
Zegeye, M. M., Lindkvist, M., Fälker, K., Kumawat, A. K., Paramel Varghese, G., Grenegård, M., . . . Ljungberg, L. U. (2018). Activation of the JAK/STAT3 and PI3K/AKT pathways are crucial for IL-6 trans-signaling-mediated pro-inflammatory response in human vascular endothelial cells. Cell Communication and Signaling, 16(1), Article ID 55.
Open this publication in new window or tab >>Activation of the JAK/STAT3 and PI3K/AKT pathways are crucial for IL-6 trans-signaling-mediated pro-inflammatory response in human vascular endothelial cells
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2018 (English)In: Cell Communication and Signaling, ISSN 1478-811X, E-ISSN 1478-811X, Vol. 16, no 1, article id 55Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: IL-6 classic signaling is linked to anti-inflammatory functions while the trans-signaling is associated with pro-inflammatory responses. Classic signaling is induced via membrane-bound IL-6 receptor (IL-6R) whereas trans-signaling requires prior binding of IL-6 to the soluble IL-6R. In both cases, association with the signal transducing gp130 receptor is compulsory. However, differences in the downstream signaling mechanisms of IL-6 classic- versus trans-signaling remains largely elusive.

METHODS: In this study, we used flow cytometry, quantitative PCR, ELISA and immuno-blotting techniques to investigate IL-6 classic and trans-signaling mechanisms in Human Umbilical Vein Endothelial Cells (HUVECs).

RESULTS: We show that both IL-6R and gp130 are expressed on the surface of human vascular endothelial cells, and that the expression is affected by pro-inflammatory stimuli. In contrast to IL-6 classic signaling, IL-6 trans-signaling induces the release of the pro-inflammatory chemokine Monocyte Chemoattractant Protein-1 (MCP-1) from human vascular endothelial cells. In addition, we reveal that the classic signaling induces activation of the JAK/STAT3 pathway while trans-signaling also activates the PI3K/AKT and the MEK/ERK pathways. Furthermore, we demonstrate that MCP-1 induction by IL-6 trans-signaling requires simultaneous activation of the JAK/STAT3 and PI3K/AKT pathways.

CONCLUSIONS: Collectively, our study reports molecular differences in IL-6 classic- and trans-signaling in human vascular endothelial cells; and elucidates the pathways which mediate MCP-1 induction by IL-6 trans-signaling.

Place, publisher, year, edition, pages
BioMed Central, 2018
Keywords
Endothelium, HUVECs, Interleukin-6 signaling, Monocyte chemoattractant Protein-1, Pro-inflammatory cytokines
National Category
Cell and Molecular Biology
Research subject
Physical Education and Sport Pedagogy; Physical Education and Sport Pedagogy
Identifiers
urn:nbn:se:oru:diva-68803 (URN)10.1186/s12964-018-0268-4 (DOI)000443839900001 ()30185178 (PubMedID)2-s2.0-85053157310 (Scopus ID)
Funder
Knowledge Foundation
Note

Funding Agencies:

Längmanska Foundation  

Foundation for Old Servants (Stiftelsen Gamla Tjänarinnor)  

Available from: 2018-09-10 Created: 2018-09-10 Last updated: 2019-03-26Bibliographically approved
Biswas, D., Cowie, A., Tozer, K., Perez, L. J., Trivedi, P., Bartlett, J. J., . . . Pulinilkunnil, T. (2018). Adverse Cardiometabolic Outcomes in Obese Patients Correlates Strongly with Defective Branched-Chain Amino Acid Catabolism. Paper presented at 37th Annual Conference of the North-American-Section (NAS) of the International-Society-for-Heart-Research (ISHR) - Cardiovascular Disease in Vulnerable Populations, Halifax, CANADA, MAY 29-JUN 01, 2018. Journal of Molecular and Cellular Cardiology, 124, 121-122
Open this publication in new window or tab >>Adverse Cardiometabolic Outcomes in Obese Patients Correlates Strongly with Defective Branched-Chain Amino Acid Catabolism
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2018 (English)In: Journal of Molecular and Cellular Cardiology, ISSN 0022-2828, E-ISSN 1095-8584, Vol. 124, p. 121-122Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Elsevier, 2018
National Category
Medical and Health Sciences Organic Chemistry
Identifiers
urn:nbn:se:oru:diva-71671 (URN)10.1016/j.yjmcc.2018.07.113 (DOI)000452246000113 ()
Conference
37th Annual Conference of the North-American-Section (NAS) of the International-Society-for-Heart-Research (ISHR) - Cardiovascular Disease in Vulnerable Populations, Halifax, CANADA, MAY 29-JUN 01, 2018
Available from: 2019-01-22 Created: 2019-01-22 Last updated: 2019-01-29Bibliographically approved
D'Souza, K., Nzirorera, C., Cowie, A., Paramel Varghese, G., Trivedi, P., Eichmann, T., . . . Kienesberger, P. (2018). Autotaxin-Lysophosphatidic Acid Signaling Contributed to Obesity-Induced Insulin Resistance in Muscle and Impairs Mitochondrial Metabolism. Journal of Lipid Research, 59(10), 1805-1817
Open this publication in new window or tab >>Autotaxin-Lysophosphatidic Acid Signaling Contributed to Obesity-Induced Insulin Resistance in Muscle and Impairs Mitochondrial Metabolism
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2018 (English)In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 59, no 10, p. 1805-1817Article in journal (Refereed) Published
Abstract [en]

Autotaxin (ATX) is an adipokine that generates the bioactive lipid, lysophosphatidic acid (LPA). ATX-LPA signaling has been implicated in diet-induced obesity and systemic insulin resistance. However, it remains unclear whether the ATX-LPA pathway influences insulin function and energy metabolism in target tissues, particularly skeletal muscle, the major site of insulin-stimulated glucose disposal. The objective of this study was to test whether the ATX-LPA pathway impacts tissue insulin signaling and mitochondrial metabolism in skeletal muscle during obesity. Male mice with heterozygous ATX deficiency (ATX +/-) were protected from obesity, systemic insulin resistance, and cardiomyocyte dysfunction following high-fat high-sucrose (HFHS) feeding. HFHS-fed ATX +/- mice also had improved insulin-stimulated AKT phosphorylation in white adipose tissue, liver, heart, and skeletal muscle. Preserved insulin-stimulated glucose transport in muscle from HFHS fed ATX +/- mice was associated with improved mitochondrial pyruvate oxidation in the absence of changes in fat oxidation and ectopic lipid accumulation. Similarly, incubation with LPA decreased insulin-stimulated AKT phosphorylation and mitochondrial energy metabolism in C2C12 myotubes at baseline and following palmitate-induced insulin resistance. Taken together, our results suggest that the ATX-LPA pathway contributes to obesity-induced insulin resistance in metabolically relevant tissues. Our data also suggest that LPA directly impairs skeletal muscle insulin signaling and mitochondrial function. Preserved insulin-stimulated glucose transport in muscle from HFHS fed ATX +/- mice was associated with improved mitochondrial pyruvate oxidation in the absence of changes in fat oxidation and ectopic lipid accumulation. Similarly, incubation with LPA decreased insulin-stimulated AKT phosphorylation and mitochondrial energy metabolism in C2C12 myotubes at baseline and following palmitate-induced insulin resistance. Taken together, our results suggest that the ATX-LPA pathway contributes to obesity-induced insulin resistance in metabolically relevant tissues. Our data also suggest that LPA directly impairs skeletal muscle insulin signaling and mitochondrial function. Preserved insulin-stimulated glucose transport in muscle from HFHS fed ATX +/- mice was associated with improved mitochondrial pyruvate oxidation in the absence of changes in fat oxidation and ectopic lipid accumulation. Similarly, incubation with LPA decreased insulin-stimulated AKT phosphorylation and mitochondrial energy metabolism in C2C12 myotubes at baseline and following palmitate-induced insulin resistance. Taken together, our results suggest that the ATX-LPA pathway contributes to obesity-induced insulin resistance in metabolically relevant tissues. Our data also suggest that LPA directly impairs skeletal muscle insulin signaling and mitochondrial function. incubation with LPA decreased insulin-stimulated AKT phosphorylation and mitochondrial energy metabolism in C2C12 myotubes at baseline and following palmitate-induced insulin resistance. Taken together, our results suggest that the ATX-LPA pathway contributes to obesity-induced insulin resistance in metabolically relevant tissues. Our data also suggest that LPA directly impairs skeletal muscle insulin signaling and mitochondrial function. incubation with LPA decreased insulin-stimulated AKT phosphorylation and mitochondrial energy metabolism in C2C12 myotubes at baseline and following palmitate-induced insulin resistance. Taken together, our results suggest that the ATX-LPA pathway contributes to obesity-induced insulin resistance in metabolically relevant tissues. Our data also suggest that LPA directly impairs skeletal muscle insulin signaling and mitochondrial function.

Place, publisher, year, edition, pages
American Society for Biochemistry and Molecular Biology, 2018
Keywords
Metabolism, insulin resistance
National Category
Medical and Health Sciences Physiology
Research subject
Health and Medical Care Research
Identifiers
urn:nbn:se:oru:diva-71323 (URN)10.1194/jlr.M082008 (DOI)000445444500002 ()30072447 (PubMedID)2-s2.0-85054086353 (Scopus ID)
Note

Funding Agencies:

Natural Sciences and Engineering Research Council of Canada 

Canadian Institutes of Health Research Project 

Banting Research Foundation 

New Brunswick Health Research Foundation 

New Brunswick Innovation Foundation 

Heart and Stroke Foundation of Canada

Natural Sciences and Engineering Research Council of Canada

Canadian Diabetes Association 

Canada Foundation for Innovation 

Available from: 2019-01-10 Created: 2019-01-10 Last updated: 2019-01-11Bibliographically approved
Paramel Varghese, G., D’Souza, K. & Kienesberger, P. (2018). Lysophosphatidic Acid Signaling in Obesity and Insulin Resistance. Nutrients, 10(4), Article ID 399.
Open this publication in new window or tab >>Lysophosphatidic Acid Signaling in Obesity and Insulin Resistance
2018 (English)In: Nutrients, ISSN 2072-6643, E-ISSN 2072-6643, Vol. 10, no 4, article id 399Article, review/survey (Refereed) Published
Abstract [en]

Although simple in structure, lysophosphatidic acid (LPA) is a potent bioactive lipid that profoundly influences cellular signaling and function upon binding to G protein-coupled receptors (LPA1-6). The majority of circulating LPA is produced by the secreted enzyme autotaxin (ATX). Alterations in LPA signaling, in conjunction with changes in autotaxin (ATX) expression and activity, have been implicated in metabolic and inflammatory disorders including obesity, insulin resistance, and cardiovascular disease. This review summarizes our current understanding of the sources and metabolism of LPA with focus on the influence of diet on circulating LPA. Furthermore, we explore how the ATX-LPA pathway impacts obesity and obesity-associated disorders, including impaired glucose homeostasis, insulin resistance, and cardiovascular disease.

Place, publisher, year, edition, pages
MDPI, 2018
Keywords
Lipidology, atherosclerosis
National Category
Medical and Health Sciences Endocrinology and Diabetes
Research subject
Health and Medical Care Research
Identifiers
urn:nbn:se:oru:diva-71322 (URN)10.3390/nu10040399 (DOI)000435182900015 ()29570618 (PubMedID)2-s2.0-85044606125 (Scopus ID)
Note

Funding Agencies:

Natural Sciences and Engineering Research Council of Canada (NSERC)

New Brunswick Health Research Foundation (NBHRF) 

Heart and Stroke Foundation of New Brunswick

Available from: 2019-01-10 Created: 2019-01-10 Last updated: 2019-01-10Bibliographically approved
Paramel Varghese, G. (2017). Innate immunity in human atherosclerosis and myocardial infarction: Role of CARD8 and NLRP3. (Doctoral dissertation). Örebro: Örebro University
Open this publication in new window or tab >>Innate immunity in human atherosclerosis and myocardial infarction: Role of CARD8 and NLRP3
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Atherosclerosis is complex inflammatory disease of the arterial wall with progressive accumulation of lipids and narrowing of the vessel. Increasing evidence suggest that inflammation plays an important role in plaque stability and often accelerate cardiovascular events such as myocardial infarction (MI). Among the vast number of inflammatory cytokines, IL-1β is known to be a key modulator in vessel wall inflammation and acceleration of the atherosclerotic process. The biologically active IL-1β is regulated by a multiprotein complex known as the NLRP3 inflammasome complex. In this thesis, we have focused on polymorphisms in the NLRP3 and CARD8 genes and their possible association to atherosclerosis and/or MI. We have also investigated the expression of inflammasome components NLRP3 and CARD8 in atherosclerosis and the role of genetic variants for the expression of these genes. The expression of NLRP3, CARD8, ASC, caspase-1, IL-1β, and IL-18 were found significantly upregulated in atherosclerotic lesions compared to normal arteries. Human carotid plaques not only express the NLRP3 inflammasome, but also release IL-1β upon exposure to lipopolysaccharide (LPS), adenosine triphosphate (ATP) and cholesterol crystals, which suggest NLRP3 inflammasome activation in human atherosclerotic lesions. Also, CARD8 was found to be important in the regulation of several inflammatory markers in endothelial cells, like RANTES, IP10 and ICAM-1. We further assessed the potential association of a CARD8 polymorphism and polymorphisms located downstream of the NLRP3 gene to the risk of MI in two independent Swedish cohorts. The CARD8 variant exhibited no association to risk of MI in either of the two cohorts. Some of the minor alleles of NLRP3 variants were associated with increased IL-1β levels and to NLRP3 mRNA levels in peripheral blood monocytic cells (PBMC). Taken together, the present thesis shows that NLRP3 inflammasome activation and increased expression of CARD8 in the atherosclerotic plaque might be possible contributors to the enhanced inflammatory response and leukocyte infiltration in the pathophysiology of atherosclerosis.

Place, publisher, year, edition, pages
Örebro: Örebro University, 2017. p. 77
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 154
Keywords
Atherosclerosis, Inflammasome, NLRP3, CARD8, Myocardial infarction, Endothelial cells, Polymorphism, IL-1β, Cytokines, Innate immunity
National Category
Other Basic Medicine
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-53482 (URN)978-91-7529-173-4 (ISBN)
Public defence
2017-01-27, Campus USÖ, hörsal C1, Södra Grev Rosengatan 30, Örebro, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2016-11-14 Created: 2016-11-14 Last updated: 2018-01-13Bibliographically approved
Paramel Varghese, G., Folkersen, L., Strawbridge, R. J., Halvorsen, B., Yndestad, A., Ranheim, T., . . . Sirsjö, A. (2016). NLRP3 Inflammasome Expression and Activation in Human Atherosclerosis. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 5(5), Article ID e003031.
Open this publication in new window or tab >>NLRP3 Inflammasome Expression and Activation in Human Atherosclerosis
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2016 (English)In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 5, no 5, article id e003031Article in journal (Refereed) Published
Abstract [en]

Background: The NLR family, pyrin domain containing 3 (NLRP3) inflammasome is an interleukin (IL)-1β and IL-18 cytokine processing complex that is activated in inflammatory conditions. The role of the NLRP3 inflammasome in the pathogenesis of atherosclerosis and myocardial infarction is not fully understood.

Methods and Results: Atherosclerotic plaques were analyzed for transcripts of the NLRP3 inflammasome, and for IL-1β release. The Swedish First-ever myocardial Infarction study in Ac-county (FIA) cohort consisting of DNA from 555 myocardial infarction patients and 1016 healthy individuals was used to determine the frequency of 4 single nucleotide polymorphisms (SNPs) from the downstream regulatory region of NLRP3. Expression of NLRP3, Apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1 (CASP1), IL1B, and IL18 mRNA was significantly increased in atherosclerotic plaques compared to normal arteries. The expression of NLRP3 mRNA was significantly higher in plaques of symptomatic patients when compared to asymptomatic ones. CD68-positive macrophages were observed in the same areas of atherosclerotic lesions as NLRP3 and ASC expression. Occasionally, expression of NLRP3 and ASC was also present in smooth muscle cells. Cholesterol crystals and ATP induced IL-1β release from lipopolysaccharide-primed human atherosclerotic lesion plaques. The minor alleles of the variants rs4266924, rs6672995, and rs10733113 were associated with NLRP3 mRNA levels in peripheral blood mononuclear cells but not with the risk of myocardial infarction.

Conclusions: Our results indicate a possible role of the NLRP3 inflammasome and its genetic variants in the pathogenesis of atherosclerosis.

Place, publisher, year, edition, pages
Hoboken, USA: Wiley-Blackwell Publishing Inc., 2016
Keywords
Inflammasome, interleukin-1b, myocardial infarction, NLRP3, polymorphism
National Category
Cardiac and Cardiovascular Systems
Research subject
Cardiology
Identifiers
urn:nbn:se:oru:diva-50441 (URN)10.1161/JAHA.115.003031 (DOI)000386711200020 ()27207962 (PubMedID)
Funder
Swedish Research Council, 6816 K2012-64X-12233-13-3Swedish Heart Lung Foundation, 20110359Magnus Bergvall Foundation
Note

Funding Agencies:

Center of Excellence for Research on Inflammation and Cardiovascular Disease (CERIC) Linnaeus Center8703

Foundation for Strategic Research, Uppdrag Besegra Stroke P581/2011-123

Strategic Cardiovascular Programs of Karolinska Institutet, Stockholm County Council ALF 20110279

Örebro University

Sigurd and Elsa Goljes Foundation

Available from: 2016-05-26 Created: 2016-05-26 Last updated: 2018-09-12Bibliographically approved
Paramel, G., Uporova, L., Halfvarson, J., Sirsjö, A. & Fransén, K. (2015). Polymorphism in the NLRP3 inflammasome-associated EIF2AK2 gene and inflammatory bowel disease. Molecular Medicine Reports, 11(6), 4579-4584
Open this publication in new window or tab >>Polymorphism in the NLRP3 inflammasome-associated EIF2AK2 gene and inflammatory bowel disease
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2015 (English)In: Molecular Medicine Reports, ISSN 1791-2997, E-ISSN 1791-3004, Vol. 11, no 6, p. 4579-4584Article in journal (Refereed) Published
Abstract [en]

Inflammatory bowel disease (IBD) is the common name for numerous relapsing inflammatory conditions, and is the collective name for Crohn's disease (CD) and ulcerative colitis (UC). The activation of the inflammasome in the pathogenesis of IBD has recently been identified, however the underlying mechanisms remain unclear. An activator of the inflammasome is double-stranded RNA-dependent protein kinase R, also termed EIF2AK2. A genetic alteration in the EIF2AK2 gene has previously been shown to be associated with Alzheimer's disease. The present study genotyped samples from a Swedish cohort of patients with IBD and healthy controls for an EIF2AK2 polymorphism. The rs2254958 polymorphism in the 5'-untranslated region of the EIF2AK2 gene was genotyped by TaqMan® single nucleotide polymorphism genotyping, followed by allelic discrimination. However, no significant association was determined between the rs2254958 polymorphism and the development of IBD, or clinical outcome. In conclusion, the results of the present study suggest that the rs2254958 polymorphism has a limited effect on the onset or progression of IBD.

Keywords
EIF2AK2; Inflammasome; NLRP3; Polymorphism; Protein kinase R; Rs2254958
National Category
Medical and Health Sciences Cancer and Oncology
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-41505 (URN)10.3892/mmr.2015.3236 (DOI)000355497100083 ()25607115 (PubMedID)2-s2.0-84924674689 (Scopus ID)
Funder
Swedish Research Council, 521-2011-2764Magnus Bergvall Foundation
Note

Funding Agencies:

Örebro University (Örebro, Sweden)

Bengt Ihre's Foundation

Nanna Svartz's Foundation

Örebro University Hospital Research Foundation

Örebro County Research Foundation

Swedish Foundation for Gastrointestinal Research

Available from: 2015-01-14 Created: 2015-01-14 Last updated: 2017-12-05Bibliographically approved
Paramel, G., Sirsjö, A. & Fransén, K. (2015). Role of genetic alterations in the NLRP3 and CARD8 genes in health and disease. Mediators of Inflammation, Article ID 846782.
Open this publication in new window or tab >>Role of genetic alterations in the NLRP3 and CARD8 genes in health and disease
2015 (English)In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, article id 846782Article in journal (Refereed) Published
Abstract [en]

The complexity of a common inflammatory disease is influenced by multiple genetic and environmental factors contributing to the susceptibility of disease. Studies have reported that these exogenous and endogenous components may perturb the balance of innate immune response by activating the NLRP3 inflammasome. The multimeric NLRP3 complex results in the caspase-1 activation and the release of potent inflammatory cytokines, like IL-1β. Several studies have been performed on the association of the genetic alterations in genes encoding NLRP3 and CARD8 with the complex diseases with inflammatory background, like inflammatory bowel disease, cardiovascular diseases, rheumatoid arthritis, and type 1 diabetes. The aim of the present review is therefore to summarize the literature regarding genetic alterations in these genes and their association with health and disease.

Place, publisher, year, edition, pages
New York: Hindawi Publishing Corporation, 2015
Keywords
NLRP3, inflammasome, polymorphism, CARD8
National Category
Immunology in the medical area
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-42795 (URN)10.1155/2015/846782 (DOI)000350655400001 ()2-s2.0-84924227184 (Scopus ID)
Note

Funding Agencies:

Magnus Bergvalls Foundation

Sigurd and Elsa Goljes Minne (Lindhes Advokatbyrå AB)

Stiftelsen Gamla Tjänarinnor

Available from: 2015-02-19 Created: 2015-02-19 Last updated: 2018-01-11Bibliographically approved
Paramel, G., Folkersen, L., Strawbridge, R. J., Elmabsout, A., Särndahl, E., Lundman, P., . . . Fransén, K. (2013). CARD8 gene encoding a protein of innate immunity is expressed in human atherosclerosis and associated with markers of inflammation. Clinical Science, 125(8), 401-407
Open this publication in new window or tab >>CARD8 gene encoding a protein of innate immunity is expressed in human atherosclerosis and associated with markers of inflammation
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2013 (English)In: Clinical Science, ISSN 0143-5221, E-ISSN 1470-8736, Vol. 125, no 8, p. 401-407Article in journal (Refereed) Published
Abstract [en]

Inflammation is a key factor in the development of atherosclerotic coronary artery disease. It is promoted through the inflammasome, a molecular machine that produces IL (interleukin)-1 beta in response to cholesterol crystal accumulation in macrophages. The CARD8 (caspase recruitment domain 8) protein modulates this process by suppressing caspase 1 and the transcription factor NF-kappa B (nuclear factor kappa B). The expression of CARD8 mRNA was examined in atherosclerotic vascular tissue and the impact on MI (myocardial infarction) of a polymorphism in the CARD8 gene determined. CARD8 mRNA was analysed by microarray of human atherosclerotic tissue and compared with transplant donor arterial tissue. Microarray analysis was performed for proximal genes associated with the rs2043211 locus in plaque. The CARD8 rs2043211 polymorphism was analysed by genotyping of two Swedish MI cohorts, FIA (First Myocardial Infarction in Northern Sweden) and SCARF (Stockholm Coronary Atherosclerosis Risk Factor). The CRP (C-reactive protein) level was measured in both cohorts, but the levels of the pro-inflammatory cytokines IL-1 beta, IL-18, TNF (tumour necrosis factor) and MCP-1 (monocyte chemoattractant protein) were measured in sera available from the SCARF cohort. CARD8 mRNA was highly expressed in atherosclerotic plaques compared with the expression in transplant donor vessel (P < 0.00001). The minor allele was associated with lower expression of CARD8 in the plaques, suggesting that CARD8 may promote inflammation. Carriers of the minor allele of the rs2043211 polymorphism also displayed lower circulating CRP and lower levels of the pro-atherosclerotic chemokine MCP-1. However, no significant association could be detected between this polymorphism and MI in the two cohorts. Genetic alterations in the CARD8 gene therefore seem to be of limited importance for the development of MI.

Place, publisher, year, edition, pages
London, United Kingdom: Portland Press, 2013
Keywords
Caspase activation and recruitment domain 8 (CARD8), cytokines, gene polymorphism, inflammasome, myocardial infarction, rs2043211
National Category
Medical and Health Sciences Genetics
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-30985 (URN)10.1042/CS20120572 (DOI)000323852600009 ()23611467 (PubMedID)2-s2.0-84880141884 (Scopus ID)
Funder
Swedish Heart Lung FoundationSwedish Research Council, 521-2009-4203 349-2007-8703
Note

Funding Agencies:

Magnus Bergvalls Foundation

Örebro University

Available from: 2013-09-27 Created: 2013-09-27 Last updated: 2018-08-27Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-4589-6440

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